The life-span of people living with HIV has dramatically increased due to effective antiretroviral therapy, and we are now faced with managing HIV as a chronic disease. Alcohol use disorder (AUD) is a significant HIV comorbidity that has been shown to negatively affect HIV disease and is associated with increased risk of HIV transmission, increased viremia, and a more accelerated progression to AIDS. Understanding the biological basis by which alcohol exacerbates HIV disease progression remains a major goal in the search for new innovative treatment strategies and the clinical management of HIV in chronically-infected populations. It is widely appreciated that the primary mediator of HIV disease is the virus, and several recent studies have begun to focus on early viral kinetics to better understand the nature of disease course. These studies have shown that rapid viral dissemination in reservoir tissues shortly after infection sets the future course for disease progression. For this reason, understanding how chronic alcohol consumption affects viral dynamics over the course of disease will provide new, multifaceted insights to the complex effects of alcohol on HIV disease. Recent studies using the SIV-infected macaque model have shown chronic binge alcohol (CBA) consumption affects early viral:host interactions leading to an increased susceptibility to intrarectal SIV challenge. Additionally, our preliminary data demonstrates CBA consumption alters viral dynamics by promoting genotypic selection and increasing viral reservoir expression. Taken together, the literature and our preliminary finding, support our central hypothesis that chronic alcohol consumption affects the establishment of founder viral reservoirs and their subsequent replication dynamics to accelerate disease progression. As part of the training of the applicant, the proposed studies will use an innovative approach to test the predictions that: 1) CBA administration increases the number and genotypic diversity of founder viral genotypes transmitted to macaques inoculated with SIVmac251, 2) CBA administration fosters the selection of SIV genotypes with increased expression kinetics in tissue reservoirs of macaques at set point, and 3) CBA administration increases compartment-specific viral expression, promoting SIV genotypic selection, despite continuous antiretroviral therapy (ART). These studies will identify how alcohol influences early viral selection and replication in the host and allow us to longitudinally assess their impact on disease progression. Furthermore, this study will aid the clinical management of HIV patients with AUD by providing evidence to optimize the selection and initiation of ART regimens and pre-exposure therapies.